Research activity of the Laboratory of Retroviral Biochemistry

HISTORY

The Laboratory of Retroviral Biochemistry (LRB) was established in 1992 by Dr. Tozser in the Department of Biochemistry of the University Medical Shool of Debrecen (now Debrecen University, Faculty of Medicine). Previously Dr. Tozser studied the specificity of HIV proteinases in the Laboratory of Dr. Stephen Oroszlan (Laboratory of Molecular Virology and Carcinogenesis, NCI-FCRDC, Frederick, MD. USA). In the following years a stong collaboration was developed between these groups (supported by the US-Hungarian Joint Fund in 1994-1997) as well as between the research groups of Dr. Irene T. Weber (now in Georgia State University) and Dr. John M. Louis (NIH) on the specificity and characteristics of various wild-type and mutant retroviral proteinases. The collaboration between LRB and Dr. Weber’s group has been recently supported by an NIH-FIRCA grant to Dr. Weber (1999-2005).

LRB, together with the other reseach groups of the Department has been incorporated into the Reseach Center for Molecular Medicine (RCMM, www.rcmm.dote.hu). The research groups of RCMM work in close collaboration with European and international partner institutions and are determined to further strengthen networking activities with leading foreign and Hungarian labs and thus embedding RCMM into the European Research Area. In 2002, the research, training and networking activities of RCMM have been recognized by the European Commission awarding the "Center of Excellence" title to the Center.

RESEARCH FOCUS

One of the major research interests of the LRB is to study the biochemistry and enzymology of retroviral replication, with an emphasis on the function and features of the viral proteinase (PR).

All replication competent retroviruses code for a PR. The function of the mature PR is critical for virion replication. The HIV-1 PR has proved to be an excellent target for antiretroviral therapy of AIDS, and various PR inhibitors are now in clinical use. However, there is a rapid selection of viral variants that are resistant to inhibitors of PR. Comparative studies of various PRs have revealed the common features of their specificity. These studies are expected to aid the rational design of broad-spectrum inhibitors effective against various retroviral proteinases, including the mutant HIV-1 enzymes appearing in drug resistance. Previously we have studied and characterized the PR of the following retrovirues: HIV-1, HIV-2, equine infectious anemia virus, human T-cell leukemia virus, bovine leukemia virus, avian myeloblastosis virus, and human foamy virus. Currently we are concentrating on the characterization of mutant HIV-1 and HTLV-1 proteinases, as well as on the characterization of murine leukemia virus and mouse mammary tumor virus proteinases. Besides the detailed characterization of various retroviral PRs, we are also involved in the efforts to prove the previously suggested early-phase function of the PR.

Recently, as a part of a large reserach project funded by the Hungarian Ministry of Education, in the frame of National Research and Development Program, entitled “Gene therapy of diseases affecting large populations: in vitro and ex vivo applications of dendritic cells in gene therapy” (Coordinator: Dr. Tozser) LRB has also been involved in the application of retroviral-derived vectors in gene therapy. The major focus of this grant is to adopt gene therapy techniques and to establish a research and technology centre for gene therapy in Debrecen, with an emphasis of using retroviral vectors. There are several human diseases that can be potentially prevented or cured by gene therapy, that is, by the introduction of a suitable gene into the target cells of the body. Recently, theoretical and practical knowledge in this field has advanced substantially, and gene therapy has been introduced into the clinical practice in the developed countries. However, these techniques require special laboratory conditions and highly trained experts. Retroviruses are ideal tools for gene therapy, especially since their life cycle includes a highly efficient integration step. Most of the retroviral genome can be substituted, and the envelope protein of retroviruses (Env) can also be changed to alter the cell tropism of the virus. The University of Debrecen was recently awarded with the grant entitled „Functional and chemical genomics in the prevention, diagnosis and treatment of specific diseases” by the National Research and Development Program in 2001. By the aid of this grant the separation and handling of dendritic cells, which play an essential role in the immune system, will be established for clinical use allowing us to perform ex vivo and in vivo experiments with the retroviral vectors.

OTHER RESEACH TOPICS

Members of the LRB are also involved in other collaborative works. These include studies of the homo- and heteroassociation patterns of ErbB oncogenes, and studies of shedding events leading to altered signal transductions through ErbB receptors. This collaboration is supported by a EU5 grant, and is performed through the reseach group of Dr. Janos Szollosi (Department of Biophysics, UD). Also, LRB is historically involved in studies on the proteolytic systems of the anterior segment of the eye, in collaboration with the team of Dr. Andras Berta (Department of Ophthalmology, UD). Another collaboration involves characterization of potyviral proteases, in collaboration with Dr. David Waugh (NCI-Frederick, USA).

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Updated: Nov 14, 2003